T U B AMKKirAN J O I ; H N A I , OK C I - I M P A I .
PATHOLOGY
Vol. 4 1 , No. 2, p p . I7rt -IK2
M m i a r v . 1084
C o p y r i g h t (£) 1964 b y T h e Williams & Wilkiiis C o .
Printed in
U.S.A.
T H E STABILITY OF EXPANSION OF T H E LUNG IN
PULMONARY PATHOLOGY
PETER GRUENWALD, M.D.
Departments of Pathology, Sinai Hospital of Baltimore and The Johns Hopkins
Baltimore, Maryland
Studies of surface forces in the pulmonary
air spaces, were limited at first to problems
of normal respiratory mechanics, and to
abnormal behavior of certain neonatal
lungs. More recent evidence, chiefly experimental, suggests that abnormalities of
surface tension are important in many other
aspects of pathology of the lung. Two
pertinent examples will be described, and
those reported by others reviewed.
It has long been known that lungs inflate
and deflate at widely different pressures,
thus producing the hysteresis apparent in a
pressure-volume curve. Inasmuch as the
ability of the pulmonary air spaces to
hold air depends largely on surface tension,
it was postulated and eventually proved that
surface tension at the interface between
moist tissue and air is not the same at
inspiration and expiration. A substance
produced by the alveolar lining cells,
and now recognized as a lipoprotein,
imparts^ surface tension which varies with
changes in surface area. The fundamental
work in this field has been reviewed by
Clements.3 The stability of lung expansion,
that is, the ability to hold air in the terminal
air spaces in the presence of little or no
transpulmonary pressure, depends on the
activity of this lipoprotein, which reduces
surface tension to very low values when the
area is reduced during expiration. This
property may be studied in specimens of
lung by means of either examining extracts
Received, June 24, 19G3; accepted for publication October 3.
Dr. Gruenwald is Associate Pathologist at
Sinai Hospital of Baltimore, and Assistant Professor of Pathology at The Johns Hopkins University.
This work was supported by research grants
• from the United Cerebral Palsy Research and
Educational Foundation, and the National Institutes of Health, Department of Health, Education, and Welfare (No. GM 08754-02).'
University,
on a surface balance with a variable area,
or by following deflation on pressurevolume curves.
METHODS OF STUDY
Changes in surface tension with varying
area are recorded with a balance illustrated
by Clements.3 The material tested usually
consists of 50 ml. of saline solution in which
3 Gm. of lung tissue has been minced. A
diagram of normal changes in activity
obtained with this instrument is illustrated
in Figure 1-4. It reveals a steady fall in
surface tension to approximately 3 dynes
per cm. when the area is reduced to one
fifth of the starting value, and a rapid
return to high levels when the area is
expanded again. Clements3 has cited
examples of similar tracings of lungs of
infants with good and poor change in
surface tension.
Pressure-volume curves of intact lungs
are best obtained with a simple apparatus
described by Avery and associates.2 Pressure
is transmitted to a cannula in the bronchus
from a reservoir containing air and water.
The pressure is regulated by means of
raising a communicating, water-filled buret,
and the amount of air leaving the reservoir
is read on the buret. Figure 1JS illustrates
the pressure-volume curve obtained in this
manner from the same lung, which was
subsequently extracted and yielded the
results in Figure L4 on the surface balance.
Other examples of good and poor stability
were previously illustrated. 6 Good and poor
stability of expansion may be distinguished
on the deflation curve at levels of 10 and
5 cm. of pressure when lungs with good
stability still contain much of the air
previously introduced at higher pressure,
whereas lungs with abnormal, poor stability
have lost much of their air content at these
17G
Feb. 1964
177
STABILITY OK LUNG EXPANSION
STILLBORN, 3350 9-
"° —- - - - -
|
T
10
20
1
p
i
i
30
40
50
60
cm. pressure
_ — —
healthy 200-gram r a t , L - 1.07
. — — — — - same specimen, after Tween 20, L - 0.19
old r a t , apparently healthy, L - 0.44
F I G . 1 (upper). Results obtained by means of 2 methods on a lung from a stillborn infant whose
weight was 3350 Gm. .1 is a tracing from a surface balance with a variable area, using an extract
of tissue. B is a static pressure-volume curve of t h e whole lung. Both loops are illustrated as
obtained in actual work, with the experimentally altered p a r a m e t e r along t h e horizontal axis, and
the resulting change along the vertical axis; both move first from left to right and then r e t u r n .
However, the 2 experiments are performed s t a r t i n g in opposite directions: in A the area is largest
a t the start, and in li the lung is collapsed, with the smallest surface area.
F i o . 2 (lower). Pressure-volume curves of 2 pairs of rat lungs. The one of the younger r a t has
normal, high stability; this is reduced to low levels by means of instillation of*Tween 20. The
change in hysteresis is illustrated by the difference in the shaded areas enclosed by the 2 curves.
The curve from the older rat manifests poor stability, although not as low as t h a t of the treated
lung. The high opening pressure of the older rat (significance unknown) produces a large hysteresis loop, but stability is independent of this.
pressures. A numerical stability index has
been derived from these observations.7
It ranges from 0 to 1.5, with an intermediate
range (0.7 to 0.8) almost free of observed
values separating good (0.8 to 1.5) and
poor (0 to 0.7) stability.
Inasmuch as stability of expansion as
determined by means of the second method
178
GRUENWAL!)
is presumably governed by surface tension
changes as demonstrated by the method
mentioned first, the 2 should yield corresponding results. It has, in fact, been
demonstrated that this is true.8 The choice
of method should depend on the type of
equipment and material available, and on
ancillary information desired which may be
yielded by 1 method and not the other. If
portions of lungs are to be examined
separately, the surface balance is clearly
superior.
Vol. 41
TABLE 1
STABILITY INDEX OF RAT LUNGS
Stability Index*
Number of
Specimen
At autopsy
Degassed
Degassed,
Twcen 20
Young adults, weight approximately 200 Gm.
22
21
23
1.07
0.97
0.85
0.19
0.25
1.02
Older adults, weight more than 250 Gm.
OBSERVATIONS
Until recently the only spontaneous
pathologic condition known to be as-"
sociated with defective stability of expansion
of the lungs was the respiratory distress
syndrome of newborn infants (atelectasis
with hyaline membranes). A deficiency of
the stability of lung expansion is probably
the cardinal lesion, and other aspects of the
disease may be secondary to it.9 In the
course of ancillary studies of animal lungs,
the following 2 examples of poor stability
of expansion were observed.
When the newly devised stability index
based on the. deflation curve, originally used
on infant lungs, was tested in a variety of
animals, it developed that it will apply,
with a slight modification, to all species
tested, with the exception of the rat.7 All
but 1 of the rat lungs tested had poor stability, with extensive air loss on deflation
to 5 cm. The specimens were obtained from
apparently healthy adult animals which
weighed somewhat more than 250 Gm., and
had been kept in the animal quarters for
some time. When cognizance was taken of
24
1
14
4
12
13
3
7
6
11
2
5
1.18
1.05
1.05
0.96
0.71
0.59
0.84
0.60
0.72
0.46
0.38
0.26
0.44
0.26
0.36
0.75
0.43
* A value of more than 0.80 indicates good
stability.
the prevalence of respiratory disease in
laboratory rats of advancing age, the lungs
of younger rats weighing less than 200 Gm.
were examined. All of these lungs had
normal stability of expansion by the standards applying to other species. Table 1 is a
stability index of all rat lungs examined,
including some additional specimens from
older rats with normal stability. Some of
these lungs were degassed by vacuum and
then inflated, and some were degassed,
gjtli|K,tum!jWWWWHHj»^»^^^
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s
KJ:
Siauau mi'iinir. in "nVfii
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wntny nfeiift&i'Yii »r ['.•"MrWin-'fy-'*r-i-
Fir;. 3. Appearance of the lungs of 3 older, apparently healthy rats when allowed
to collapse at autopsy. There are airless portions scattered among others with residual
air.
Feb. 1904
STAHIL1TV OK LUNG EXPANSION
followed by the instillation of a solution of
Twcen 20 through the trachea, and then
inflated again. Twcen 20 is a detergent
which is known to inactivate the characteristic surfactant in the lungs, and thus
179
produces very poor stability of expansion.17
Kigure 2 demonstrates the normal pressurevolume curve of a younger rat, the curve
indicating poor stability after instillation of
Twcen 20 in the same specimen, and supcr-
Fio. 4.. Sec tin lis from » lung of a rat appearing like tlic ones in Figure 3. .'I (upper)
illustrates the normal residual air; Ii (lower), extensive atelectasis but no inflammatory reaction. X- 350.
180
GRUENWALD
imposed upon these the curve of an olderrat with poor stability; it is apparent that
the deflation curve of the latter is intermediate between the other 2. Upon opening
the chest it was found that some lungs of
older rats revealed scattered areas of collapse
(Fig. 3), and these lungs had poor stability.
The curves intermediate between good and
very poor stability (Fig. 2) are apparently
the result of measuring a combination of
stable and unstable areas. It is very likely
that poor stability of expansion, present in
scattered areas of the lungs of apparently
healthy older rats, is an early manifestation
of chronic murine pneumonia." At this stage
the lungs reveal microscopically only atelectasis, but no inflammatory reaction (Fig. 4).
Pattle and Burgess12 found poor stability in
some areas of the lungs of rats and mice, but
in their cases marked acute or chronic inflammatory changes were present.
The second observation of poor stability
of expansion was made on the lungs of
rabbits killed immediately after treatment
with phosgene intermittently for 4 hr. for
purposes of another study. 5 Unfortunately
only 2 observations are available, and there
has been no opportunity to obtain more.
The following are the stability index values
for all rabbits examined in this laboratory:
Normal newborn—1.00, 1.04; Normal adult
—0.98, 0.98, 0.98, 1.00, 1.02; Phosgene
treated adult—0.54, 0.78.
As was the case in the rats with abnormal
stability, upon opening the chest at autopsy,
the lungs of the phosgene-treated rabbits
had collapsed areas interspersed with aerated
ones. Pattle and Burgess12 found no alteration of stability in 4 rats treated with phosgene and surviving for from 6 hr. to 3 days
after termination of the treatment. Differences in intensity and timing of the insult
are probably responsible for this discrepancy
of results.
Other authors have recorded poor surface
activity with compression of the area in
experimental animals: ligation of the pul- monary artery in dogs,4 prolonged use of
cardiopulmonary bypass with pump oxygenator in dogs,16'1G intratracheal administration of noxious agents, and spontaneous
disease in laboratory rodents,12 experimental
Vol. 41
pulmonary edema in dogs," oxygen poisoning in rabbits, 10 and atelectasis produced by
pneumothorax in rabbits. 1 In several of
these instances differences were noted between areas of the same lung which at
autopsy were airless or aerated. 1,12 ' 13
Sutnick and Solon"14 were the first to make
similar observations in human autopsy
material, and noted differences in surface
activity between portions of lungs which
differed grossly in air content.
DISCUSSION AND CONCLUSIONS
Two significant facts emerge from the
present observations and those of others
quoted above. A number of experimental
conditions and diseases which may occur
in man result in loss of the characteristic
surface activity which accounts for stability
of expansion of the lungs. This loss may be
an early or late manifestation of the disease.
Atelectasis may cause or be caused by this
loss of activity. It has been pointed out 1
that airlessness is probably not the cause
of loss of activity, but more likely poor
vascular perfusion of collapsed areas. In
order to correlate pathologic findings with
abnormalities of pulmonary function, it
will be necessary to study pulmonary surface forces more extensively than has been
done in the past, and make such studies
part of the pathologic examination of pulmonary disease.
The second point brought out by recent
findings is one of localization. In early work
on pulmonary surface forces, this was neglected because both healthy laboratory
animals and newborn infants, which were
the 2 types of material investigated, have
rather uniform lungs in this respect. I t is
now clear that focal distribution of abnormal
surface activity must be taken into account.
It will be noted that throughout this report reference has been made to the presence
or absence of the characteristic surface
activity in the pulmonary air spaces, but
not to the presence or absence of the active
material. It is known that in addition to the
presence of this material, certain conditions
must be met in order to obtain the characteristic surface activity, and that a number
of substances are capable of inhibiting the
Feb. 1964
181
STABILITY OF LUNG EXPANSION
activity even though the specific material
is present. It is thus quite possible that in
many of the instances iu which we can demonstrate poor stability of expansion the
characteristic material is not absent, but
rather is inactivated.
Examination of lungs in human pathology
or after experiments by means of one of the
methods mentioned above must be preceded
by a detailed gross inspection for variations
in air content. If a lung is to be rendered
gas-free by vacuum, examination must of
course precede this procedure. If pieces of
tissue are to be extracted for examination
on the surface balance, proper selection is
essential; a small admixture of tissue with
normal activity may cover up a lack of
activity in the remainder of the specimen.
This has actually been observed in several
laboratories when active and inactive extracts were mixed (unpublished). It is conceivable that the opposite effect might occur
if the inactive specimen contains a potent
inhibitor.
The choice of method will often depend on
technical rather than scientific considerations. A surface balance suitable for the
determination of changes of tension with
compression of the area is not available
commercially; a few workshops make these
instruments, and they are costly and require expert and meticulous attention. For
the purposes discussed here it would be
sufficient to determine the highest and lowest
tension with change in area, rather than to
record loops as illustrated in Figure 1/1.
With increasing demand, a sufficiently simple instrument may become available.
Equipment for determining pressure-volume
curves, on the other hand, may readily be
assembled at minimal expense. This, however, is useful only for intact and relatively
small lungs. It discloses the over-all properties of a lung (Fig. 2) and can not be used for
the examination of portions of lungs which
the pathologist might wish to investigate.
SUMMARY
Deficiency of the normal stability of
expansion of the lung, which is contingent
upon the activity of a peculiar, area-dependent surfactant at the respiratory sur-
faces, occurs in a variety of pathologic and
experimental conditions. Examples . from
work reported here and from the literature
attest to this.
In investigation of pulmonary pathology,
it is therefore desirable to include determinations of cither the surface activity of
lung extracts or the pressure-volume characteristics of whole lungs.
SUMMAKIO IN INTERLIXGUA
Le stabilitate normal del expansion pulmonari dependc del activitate de un peculiar
surfactante al superficies respiratori. Iste
surfactante de su parte depende del area.
Dcfiencientia del stabilitate del expansion
pulmonari occurre in un varietate de conditiones pathologic e experimental. Isto es
documentate per exemplos reportate in le
presentc communication e per alteres trovabile in le litteratura.
In investigationes de statos pathologic del
pulmon il es per consequente desirabile includer determinationes del activitate superficial de extractos pulmonar o del characterristicas de pression-volumine del pulmon
total.
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